Changes in the expression of nuclear β-catenin are responsible for tumorigenesis. Beta-catenin acts synergistically with the TGF-β/BMPs pathway. This interaction leads to greater dentin deposition and may explain the differences between distinct tooth morphologies and hamartomas. The aim of this study was to investigate the role of β-catenin, BMP4 and TGF-β in the development of odontomas. This cross-sectional, retrospective, immunohistochemical study evaluated 30 compound odontomas, 30 complex odontomas and 17 tooth germs. The results showed that BMP4 and TGF-β were more immunoexpressed in the ectomesenchyme of complex odontomas (median = 33.7, p < 0.001; median = 76.4, p = 0.002, respectively). Higher immunoexpression of BMP4 and TGF-β was also observed in the epithelium of tooth germs (median = 2.0, p < 0.001; median = 120.3, p < 0.001, respectively). TGF-β and BMP4 showed a positive and significant correlation (p < 0.001). Both TGF-β and BMP4 were positively correlated with nuclear β-catenin in ectomesenchyme (p = 0.047 and p = 0.023, respectively). Developing teeth exhibited higher concentrations of the proteins studied in odontogenic epithelium, especially during the bud and cap stages. Higher immunoexpression in odontomas occurred mainly in the ectomesenchyme. We therefore suggest that changes in the ectomesenchyme can lead to the development of odontomas.